The technical field of this invention is the treatment of neurodegenerative and neuromuscular disorders and, in particular, the treatment of Amyotrophic Lateral Sclerosis (ALS).
ALS is a progressive neurological disorder characterized by muscle fiber atrophy resulting from the degeneration of motor neurons in the spinal column and brain. ALS affects approximately 30,000 US citizens, with only ≈10% of cases being classified as the familial form of ALS. In a subset of familial patients with mutations in the metabolic enzyme superoxide dismutase 1 (SOD1), the pathological progression may be attributed to an unknown gain of function associated with a mutant form of the enzyme, i.e., is SOD1 dependant. However in the majority of ALS cases the SOD1 gene contains no mutations, the activity of the SOD1 enzyme is normal, and the mechanism of disease pathology is unknown, i.e., not SOD1 dependent. Therefore, the remaining 90% of ALS cases are classified as sporadic cases, with no well-characterized genetic component or causal agent.
While the role of infiltrating lymphocytes is poorly understood, recent work suggests that infiltrating T cell populations are neuroprotective. In recent studies mSOD1 mice were crossed with RAG2−/− mice, which have no mature T or B cells, (mSOD1/RAG2−/−) or with CD4−/− mice which lack CD4+ T cells. Both the mSOD1/RAG2−/− and mSOD1/CD4−/− transgenic mice have a significantly shorter lifespan (16 vs. 24 weeks) suggesting a neuroprotective effect of infiltrating lymphocytes.
However, it has recently been discovered that certain populations of infiltrating lymphocytes are not neuroprotective but rather are contributing factors in the progression of neurological disorders. In particular, infiltration of CD8-positive (CD8+) T cells have been found to contribute to progressive neurodegeneration, especially in diseases such as Amyotrophic Lateral Sclerosis (ALS).